The Zscan4 gene was identified by expression profiling of all preimplantation stages of mouse embryos using a large-scale cDNA sequencing project (Ko et al., Development 127:1737-1749, 2000; Sharov et al., PLoS Biol 1:E74, 2003) and DNA microarray analysis (Hamatani et al., Dev Cell 6:117-131, 2004). In mice, Zscan4 consists of 6 paralog genes (Zscan4a to Zscan4f) and 3 pseudogenes (Zscan4-ps1 to Zscan4-ps3) clustered on an approximately 850 kb region of chromosome 7. Among the six paralogs, the open reading frames of Zscan4c, Zscan4d, and Zscan4f encode a SCAN domain as well as all four zinc finger domains, suggesting their potential role as transcription factors. A high expression peak of Zscan4 marks the late 2-cell stage of mouse embryos. Zscan4 expression, normally below detection threshold in blastocysts, is reactivated in vitro in a small fraction of ES cells in culture. Although all six Zscan4 paralogs are expressed in ES cells, Zscan4c is the predominant paralog, whereas Zscan4d is the predominant paralog in 2-cell embryos (Falco et al., Dev Biol 307:539-550, 2007; PCT Publication No. WO 2008/118957).
It has previously been demonstrated that Zscan4 is associated with a unique transient state in undifferentiated ES cells in which other 2-cell embryo-specific genes are activated. Zscan4 is essential for long-term maintenance of genomic integrity and for mediating a regulated telomere recombination in normal undifferentiated ES cells (Zalzman et al., Nature 464(7290):858-863, 2010).
The pancreas has been a focus of intensive research in regenerative medicine because type I diabetes could potentially be cured if insulin-producing pancreatic cells are supplemented. Thus, identifying progenitor cells that could give rise to endocrine and exocrine cells in the adult human pancreas is desirable. The existence of progenitor cells in pancreatic ducts has previously been speculated based on the observation that all pancreatic cells develop from progenitor cells that form duct-like structures in the embryonic pancreas (Oliver-Krasinski and Stoffers, Genes Dev 22:1998-2021, 2008). However, little is known about whether undifferentiated progenitor cells exist in pancreatic ducts or if differentiated cells can redifferentiate to other cells types (Aguayo-Mazzucato and Bonner-Weir, Nat Rev Endocrinol 6:139-148, 2010). One major hurdle to the identification of resident stem cells in the pancreas is that this tissue type that has a very low rate of spontaneous self-renewal, thus it is expected that the number of pancreatic stems cells, if any, is very low (Barker and Clevers, Gastroenterology 138:1681-1696, 2010). Another challenge to identifying resident stem cells is the lack of specific tissue stem cell markers, which has hampered the progress in identifying such a rare cell type in human pancreatic tissues.